Organic and Medicinal Chemistry International Journal ISSN 2474-7610 Research Article Organic & Medicinal Chem IJ Volume 8 Issue 3 - May 2019 Copyright © All rights are reserved by Krishna Sarmapathy DOI: 10.19080/OMCIJ.2019.08.555739 NNRTI (Non-Nucleoside Reverse Transcriptase Inhibitor) Drug AZT and Their Preparation & Determination A Patent Evaluation of Efavirenz Krishna sarmapathy* Department of Organic Chemistry, Head IPL research Centre, India Submission: April 04, 2019; Published: May 20, 2019 *Corresponding author: Krishna Sarmapathy, Department of Organic Chemistry, Head IPL research Centre, India Abstract Human immunodeficiency virus type-1 (HIV-1) is the causative agent for the transmission and development of the acquired immunodeficiency syndrome (AIDS).Efavirenz (II) a potent NNRTI, is a significant component of a very effective (protease sparing) regimen when co administered with AZT and 3TC [1]. Importance of Efavirenz led to the development of several strategies for its synthesis, and preparation was described in this attemptpaper, the well world in thegreat handling potential of drug environment Efavirenz friendly still inaccessible Efavirenz to development millions of people especially because Merck. of its We atom have economy surprisingly and toxic found [2]. that Patent compound evaluation of on process patents and well defined summary of patents . During the course of drug development most of the world pharmaceutical companies Efavirenz can be prepared in good yield and high purity by Cyclisation of compound of (S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1- trifluorobut-3-yn-2-ol with urea. Finally, Analytical method for determination Efavirenz has the absorbance maxima at 561 nm for the first order derivativeKeywords: visible-Spectrophotometric method. HIV-1; AIDS; AZT; DTG Benz oxazinones; Efavirenz; Urea; Cyclisation; crystallization; UV; spectrophotometric method; ART; CPA Efavirenz, DMP 266 Efavirenz, L-743725((+)-enantiomer), DMP-266, L-741211(ra- to 82% of those on EFV. Longer term, DTG was projected to cemate), L-743726, Stocrin, Sustiva (S)-(-)-6-Chloro-4-(cyclo- 90% of people on DTG would be virally suppressed compared increase the proportion of people living with HIV on treatment - propylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-ben researchers found DTG had the potential to avert 13,000 new HIV antiretroviral treatment (ART) to treat HIV, which is currently who were still alive after five years from 76.7% to 83%.Crucially, zoxazin-2-one. Now India recommends efavirenz (EFV)- based - es on DTG are now lifting in India, generic versions of DTG are infections over five years, equivalent to a 20% decrease in HIV cheaper than DTG-based ART. However, as pharmaceutical licens costs. When all factors are taken into account, care costs for the incidence, resulting in a saving of US$800,000 in projected care likely to bring its cost close to that of EFV. Research from the USA - number of people initiating treatment on EFV were estimated to and Europe, where DTG is recommended as the first option for be US$139 million at two years and US$590 million at five years. treatment, suggests DTG has more tolerable side effects, can en to drug resistance [3]. In comparison, the care costs for DTG at two years was found to be able people to suppress HIV levels quickly and is less likely to lead lower at US$137 million and cost-neutral at five years at US$590 million. Cost increases linked to DTG were identified by the model, longer when on DTG, incurring greater lifetime care costs [4]. As a result, DTG’s use in these countries has substantially although these reflect the fact that more people are likely to live reduced the number of people who fail first-line treatment and As a result, the authors recommend that when generic DTG mathematical simulation model of how HIV can advance and how are lost to care or require a switch to second-line ART. Using a International AIDS Society, examined the clinical and economic becomes available in India, if priced at no more than $180 per it responds to treatment, the study, published by the Journal of impact DTG could have on India’s HIV response in comparison person per year, it would be cost-effective for India to switch to DTGThe as first research-line treatment. is particularly timely as India changed its treatment guidelines in 2017 to recommend that people living to EFV. Researchers found using DTG as the first option for HIV treatment would be cost-effective, and potentially cost-saving, for India’s public health system. At 48 weeks, modellingsuggests with HIV start treatment as soon as possible, regardless of their Organic & Medicinal Chem IJ 8(3): OMCIJ.MS.ID.555739 (2019) 001 Organic and Medicinal Chemistry International Journal of the commercial importance of Efavirenz there remains need CD4 count. As a result, the cost of ART is becoming an increasingly with respect to yield, purity, plant feasibility etc. Hence in view central consideration to ensure treatment can be provided to all the manufacture of optically pure Efavirenz. The synthesis of thoseMerck now Synthesis eligible. of Efavirenz- History for an improved process. US 6 028 237 discloses a process for efavirenz and structurally similar reverse transcriptase inhibitors making it the 14th approved antiretroviral drug. Efavirenz is a the corresponding PCT International Patent Application WO Efavirenz was approved by the FDA on September 21, 1998, are disclosed in US Patents 5,519,021, 5,663,169, 5,665,720 and clinically for use in the treatment of HIV infections and AIDS. non-nucleoside reverse transcriptase inhibitor being studied Efavirenz chemically known as (-) 6-Chloro-4-cyclopropylethynyl- 95/20389, which published on August 3, 1995 [7]. 4-trifluoromethyl- 1, 4- dihydro-2H-3, 1-benzoxa zin-2-one, is a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI).A number of compounds are effective in the treatment of that causes progressive destruction of the human immune the human immunodeficiency virus (HIV) which is the retrovirus system. Effective treatment through inhibition of HIV reverse transcriptase is known for non- nucleoside-based inhibitors. Benz oxazinones have been found to be useful non-nucleoside- based inhibitors of HIV reverse transcriptase.(-) β-chloro^- cyclopropylethyny M-trifluoromethyl-l ,4-dihydro-2H-3,l -ben transcriptase resistance [5]. Due to the importance of (-)6-chloro- zoxazin-2-one (Efavirenz) is efficacious against HIV reverse 4-cyclopropylethynyl-4-trifluoromethyl-l,4-dihydro-2H-3,l-ben zoxazin-2- one, economical and efficient synthetic processes for its production needs to be developed. The product patent column-29, involving cyclisation of racemic mixture of 2-(2-amino- US5519021. discloses the preparation of Efavirenz, in Example-6, 5-chlorophenyl)-4- cyclopropyl-l,l,l-trifluoro-3-butyn-2-ol using racemic Efavirenz. Further, resolution of the racemic Efavirenz is l, l ‘-carbonyl diimidazole as carbonyl delivering agent to give carried out using (-) camphanic acid chloride to yield optically pure Figure 2: Enantioselective addition of lithium acetylide in the future, 1998, 23(2), 133-141 discloses process for manufacture Efavirenz. However, research article published in the Drugs of the synthesis of HIV drug Efavirenz. of optically pure Efavirenz. The process involves cyclisation of racemic 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-l, 1, l-trifluoro-3-butyn-2- ol using 1, 1-carbonyldiimidazole as carbonyl delivering agent to give racemic Efavirenz and further resolution by (-) camphanic acid chloride [6]. Similarly, research stereo selective synthesis of Efavirenz (95%yield, 99.5%ee), as article published in Synthesis 2000, No. 4, 479-495 discloses Figure 3: Efavirenz (95%yield, 99.5%ee). shown below (Figure 1). Additionally, the asymmetric synthesis of an enantiomeric benzoxazine by a highly enantioselective acetylide addition et al., Tetrahedron Letters 1995, 36, 8937-8940, as well as the and cyclization sequence has been described by Thompson, PCT publication, WO 96/37457, which published on November which disclose various aspects of the synthesis of(-)-6-chloro- 28, 1996.Additionally, several applications have been filed Figure 1: Efavirenz ,DMP 266. 4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1- Even though many prior art processes report method for benzoxazin-2-one including: 1) a process for making the chiral the preparation of Efavirenz, each process has some limitations alcohol, U.S.S.N. 60/035,462, filed 14 January 1997; 2) the chiral additive, U.S.S.N. 60/034,926, filed 10 January 1997; 3) the 002 How to cite this article: Krishna sarmapathy. NNRTI (Non-Nucleoside Reverse Transcriptase Inhibitor) Drug AZT and Their Preparation & Determination A Patent Evaluation of Efavirenz. Organic & Medicinal Chem IJ. 2019; 8(3): 555739. DOI: 10.19080/OMCIJ.2019.08.555739 Organic and Medicinal Chemistry International Journal produce a kilogram of EFV. Current production processes are more cyclization reaction, U.S.S.N. 60/037,059, filed 12 February 1997; and the anti-solvent crystallization procedure, U.S.S.N. 60/037,385 efficient; roughly 3 kg of EFV is now produced for each 1 kg of CPA (Figures 2 & 3) [8]. of CPA to the cost of EFV API production has fallen from as high as filed 5 February 1997 and .S.S.N. 60/042,807 filed 8 April 1997 used. From this it can be roughly estimated that the contribution USD425/kg to about USD17-20/kg today [11]. Efavirenz has been obtained by two related ways: 1) The means of Na2CO3 in toluene gives the expected anilide (III), acylation of 4-chloroaniline (I) with pivaloyl chloride (II) by which is acylated with ethyl trifluoroacetate by means of butyllithium in THF yielding, after hydrolysis with HCl, 2′-amino- 5′-chloro-2,2,2-trifluoroacetophenone (IV). The benzylation of the protected acetophenone (VI), which is regioselectively (IV) with 4-methoxybenzyl chloride (V) in basic alumina affords condensed with cyclopropylacetylene (VII) [obtained by cyclization of 5-chloro-1-pentyne (VIII) by means of butyllithium of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol (IX) giving the in cyclohexane] by means of butyllithium in THF in the presence (S)-isomer of the tertiary alcohol (X) exclusively.